Androgen Receptor Inhibitor (ARI) Incremental Adverse Event (AE) Estimator

Assessing the risk of incremental adverse events associated with androgen receptor inhibitors in the treatment of mCSPC

Androgen receptor inhibitors (ARIs) delay the progression of metastatic castration-sensitive prostate cancer (mCSPC). An important treatment goal in mCSPC is to optimize safety to prolong time on treatment and maintain patient quality of life. Understanding differences in the tolerability profiles of ARIs is important to properly assess the risk-benefit profile of the intended therapeutic agent and for informed clinical decision-making. This exploratory ARI incremental adverse event (AE) Estimator leverages data from pivotal trials of ARIs combined with androgen deprivation therapy (ADT) (darolutamide [DARO] + ADT, apalutamide [APA] + ADT and enzalutamide [ENZA] + ADT in mCSPC), to estimate the incremental risk of AEs* associated with the use of these ARIs + ADT vs. control (ADT) in mCSPC.
 

No head-to-head randomized controlled trials have been conducted to compare the efficacy and safety of DARO + ADT, APA + ADT or ENZA + ADT in mCSPC treatment. Based on the results of indirect treatment comparisons of these ARIs, there is no conclusive evidence of differences in efficacy between the ARIs when combined with ADT. However, differences in tolerability may exist.

Instructions for use:

1. Select
   ARI + ADT of interest.
2. Enter
   the number of mCSPC patients in your practice.
3. Review
   the estimated number of incremental AEs that may be experienced on an ARI + ADT vs. ADT alone, based on the number of mCSPC patients in your practice receiving the treatment.

How were these estimates derived?

This ARI incremental AE Estimator is based on a Number Needed to Harm (NNH) analysis conducted using data from ARI + ADT clinical trials. The analysis evaluated the incidence rates of comparable all grade AEs reported in the primary publications of ARANOTE, TITAN and ARCHES, the pivotal studies that demonstrated the treatment effects of DARO + ADT, APA + ADT and ENZA + ADT, for the treatment of mCSPC. The incidence rates for each respective AE* in the active arm and the control arm (Table 1) were used to calculate the NNH, a trial-based measure that estimates the number of patients who need to receive treatment before a harmful outcome is expected to occur with the intervention, compared to the control arm.

A higher NNH reflects a

NNH values and what they suggest:

Negative NNH suggests higher incremental risk in placebo. For simplicity, negative NNH is interpreted as no additional risk of an event.

*Note: All grade AEs were used as higher incidence rates of these events allow a more complete calculation of NNH across studies. AEs were selected if they were consistently reported in at least 2 studies. AEs that yielded negative NNH across all studies were not included. Side-by-side presentation of incremental AEs in the Estimator require AEs to be reported for both ARI + ADT. As TITAN did not report cognitive impairment, ARCHES did not report anemia and increased alkaline phosphatase and ARANOTE did not report asthenia, these AEs are not presented side-by-side.

The ARI incremental AE Estimator extrapolates the calculated NNH to a case load of mCSPC patients receiving the specified ARI + ADT. As NNH = number of patients who need to receive an intervention before an incremental AE occurs with the intervention vs. control:

Therefore, the incremental AE estimated in the ARI incremental AE Estimator is calculated based on the number of mCSPC patients entered, divided by the NNH. 

As no head-to-head randomized controlled trials have been conducted of DARO + ADT, APA + ADT or ENZA + ADT, the results of the ARI incremental AE Estimator should be considered exploratory and interpreted with caution. Prospective head-to-head comparisons are needed to confirm these findings. As the ARI incremental AE Estimator relies on cross-trial data comparisons, the limitations inherent to any indirect treatment comparison apply. ARANOTE had a smaller patient sample size than TITAN or ARCHES and heterogeneity in trial design could introduce uncertainty. Baseline characteristics varied across the analyzed trials, with ARANOTE enrolling more patients with high volume disease and higher median baseline PSA. TITAN and ARCHES included patients who received prior docetaxel and these patients were excluded from ARANOTE. In TITAN and ARCHES, subjects with a history of seizure or any condition that may predispose to seizure were excluded, whereas ARANOTE did not have this exclusion criterion. The NNH analysis was also based on the primary reports of the studies, which had different median follow-up times (ranging from 14.4 months [ARCHES] to 25.3 months [ARANOTE]). Time dependency in the occurrence of AEs may affect inference.

This tool provides exploratory estimates of incremental adverse events potentially associated with specified ARIs + ADT compared with ADT in mCSPC. Estimates are derived from published pivotal trials that were not conducted head‑to‑head and have differences in study design, populations, endpoints, and follow‑up. As such, the estimated outputs may not be generalized to individual patients or clinical settings. This tool is intended solely for use by healthcare professionals for general informational purposes and does not provide medical advice, diagnosis, treatment recommendations, or a substitute for clinical judgment. Do not rely on the estimated outputs for clinical decision‑making without independent verification and consideration of the full evidence base. Bayer makes no representation or warranty, express or implied, regarding the accuracy, completeness, or fitness for a particular purpose of the tool or its estimated outputs and disclaims any duty to update. By using the tool, you acknowledge these limitations and agree that Bayer and its affiliates are not liable for any decisions or actions taken or not taken in reliance on the tool’s estimated outputs.

*Note: All grade AEs were used as higher incidence rates of these events allow a more complete calculation of NNH across studies. AEs were selected if they were consistently reported in at least 2 studies. AEs that yielded negative NNH across all studies were not included. Side-by-side presentation of incremental AEs in the Estimator require AEs to be reported for both ARI + ADT. As TITAN did not report cognitive impairment, ARCHES did not report anemia and increased alkaline phosphatase and ARANOTE did not report asthenia, these AEs are not presented side-by-side. 

PP-PF-ONC-CA-0127-1